The genomic complexity of mammals, particularly humans, allows for numerous genetic and physiological changes during conception, development of the fetus, and during adult life. Subsequently, pathologic changes may occur, due to autoimmune diseases, exposure to mutating agents, and the like. In addition, there are various recessive genes, which can result in diseases when the resulting progeny is homozygous for the recessive trait. For the most part, individuals having a variety of genetic diseases or pathological indications associated with autoimmune diseases, such as diabetes, have, for the most part, been dependent upon the administration of drugs. Drugs have not been entirely satisfactory for a number of different reasons. Frequently, the drugs have side effects which are detrimental to the host and result in pathological events. For some diseases, drugs are merely palliative or nay not even be available. In other situations, regular administration of drugs can be difficult to maintain, particularly with the elderly or mentally impaired, who find it difficult to perform a strict regimen.
With The advent of recombinant technology, the possibility of modifying endogenous cells or cells which can be safely administered to a host has offered new avenues of investigation for therapeutic treatments. However, there are many concerns related to the use of gene therapy. In some cases, one is solely concerned with introducing cells into the host which can function in place of defective wild-type cells. In other situations, one may wish to provide cells which can produce a secreted product which can then fulfill a desired function. However, in normal physiological operation, the secretion of product is usually controlled based on need and, frequently, may involve providing a localized concentration of the secreted product, rather than a systemic availability. It is therefore of substantial interest to be able to develop gene therapies, which can meet manifold therapeutic needs as required by the sick and impaired.
The levels of production of proteins by human cells varies by as much as 1 to 10.sup.6 fold during development and in response to physiologic and pathologic stimuli. (E. H. Davidson, Gene Activity in Development 1986, 3rd Edition, Academic Press, Orlando, Fla.) Since any protein if overexpressed nay have toxic and harmful effects, it is essential that any introduced gene be carefully regulated.
Furthermore, there is usually a minimum level of therapeutic effect. By monitoring the level of the protein product in the tissue, organ or vascular system, in a system subject to extrinsic control, one can determine the level of the protein product, and use the extrinsic control to provide the desired level.
Besides intracellular opportunities for therapy, there are also possibilities where control of extracellular events may be of interest. In a variety of situations, such as homing, blood coagulation, clot dissolution, cell activation, and the like, the ability to bring together two or more different proteins rapidly could provide for new opportunities for controlling physiology and therapies.